Is There a Critical Period for the Developmental Neurotoxicity of Low-Level Tobacco Smoke Exposure?


Secondhand tobacco smoke exposure in pregnancy increases the risk of neurodevelopmental disorders. We evaluated in rats whether there is a critical period during which tobacco smoke extract (TSE) affects the development of acetylcholine and serotonin systems, prominent targets for adverse effects of nicotine and tobacco smoke. We simulated secondhand smoke exposure by administering TSE so as to produce nicotine concentrations one-tenth those in active smoking, with 3 distinct, 10-day windows: premating, early gestation or late gestation. We conducted longitudinal evaluations in multiple brain regions, starting in early adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure in any of the 3 windows impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although the adverse effects were seen for all 3 treatment windows, there was a distinct progression, with lowest sensitivity for premating exposure and higher sensitivity for gestational exposures. Serotonin receptors were also reduced by TSE exposure with the same profile: little effect with premating exposure, intermediate effect with early gestational exposure and large effect with late gestational exposure. As serotonergic circuits can offset the neurobehavioral impact of cholinergic deficits, these receptor changes were maladaptive. Thus, there is no single 'critical period' for effects of low-level tobacco smoke but there is differential sensitivity dependent upon the developmental stage at the time of exposure. Our findings reinforce the need to avoid secondhand smoke exposure not only during pregnancy, but also in the period prior to conception, or generally for women of childbearing age.





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Publication Info

Slotkin, Theodore A, Ashley Stadler, Samantha Skavicus, Jennifer Card, Jonathan Ruff, Edward D Levin and Frederic J Seidler (2017). Is There a Critical Period for the Developmental Neurotoxicity of Low-Level Tobacco Smoke Exposure?. Toxicological sciences : an official journal of the Society of Toxicology, 155(1). pp. 75–84. 10.1093/toxsci/kfw180 Retrieved from

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Theodore Alan Slotkin

Professor of Pharmacology and Cancer Biology

We study the interaction of drugs, hormones and environmental factors with the developing organism, with particular emphasis on the fetal and neonatal nervous system. The role of biochemical factors mediating development of nerve cells and other types of tissue is a major thrust, since they influence the subsequent structural and physiological status of critical organ systems. Ongoing projects comprise five areas: (1) Mechanisms regulating development of synapses - role of endocrine and other trophic factors, intracellular messengers in developing cells, control of target organ differentiation by neural input; (2) Adverse effects of exogenous agents on development, with an emphasis on identification of mechanisms by which behavioral or physiological damage occurs - drugs of abuse (especially nicotine), hormonal imbalances, environmental contaminants (especially pesticides), food additives, intrauterine growth retardation, fetal and neonatal hypoxia; (3) Control of fetal and neonatal cardiovascular and respiratory function by the immature nervous system - normal physiological mechanisms, responses to stress, factors mediating the transition from fetal to neonatal function, reactivity during delivery, Sudden Infant Death Syndrome; (4) Breast cancer cell growth regulation - role of hormone and neurotransmitter receptors converging on common cell signaling mechanisms, and targeting of these receptors for cancer therapeutics.

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